This invention relates to a new class of antibiotics which may be generically represented by the following structural formula (I): ##STR1## wherein A is S, O, SO, or NR.sup.7 (R.sup.7 is selected from the group consisting of hydrogen, alkyl, formyl, acyl, thioacyl, alkyl sulfonyl and aryl sulfonyl); X is OH, .dbd.O, SH, or .dbd.NH, NH.sub.2, NHR.sup.7 ; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl (mono- and bicyclic) wherein the heterocyclic moiety comprises 4-10 ring atoms and the hetero atom (or atoms) is O, N or S; and wherein the ring or chain substituent is selected from: amino, carboxy, hydroxy, alkoxy, carbalkoxy, lower alkyl, heteroaryl, and substituted amino such as mono- and dialkylamino, and acylamino; and perhaloalkyl; with the proviso that, when X is .dbd.O or .dbd.NH, the substituent R.sup.2 is absent; examples of such substituents R.sup.1 and R.sup.2 are methyl, trifluoromethyl, phenyl, substituted phenyl, benzyl and the like; R.sup.3 is selected from the group consisting of hydrogen, alkoxy, halogen, such as fluoro and bromo and alkylthio; R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, and alkyl and R.sup.6 is COXR.sup.8, wherein X is oxygen or sulphur and R.sup.8 is conventionally known in the penicillin and penicillin-like art and is, inter alia, representatively selected from the group consisting of hydrogen, trialkylsilyl, and the pharmaceutically acceptable salt, ester and amide moieties known in the art such as sodium, potassium, pivaloyloxymethyl, and the like.
There is a continuing need for new antibiotics. For unfortunately there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms--they are generally not effective against a broad range of pathogens.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems. It will be recognized from the above generic representation (I) that the principal novel feature of the compounds of the present invention is the 6-substituted methyl substituent, which position heretofore in the penicillin art has always been amino or substituted amino for compounds of high activity. It will also be noted, except where expressly stated, that the balance of the penicillin or penicillin-like structure (I) is well-known in the relevant art.
Thus, it is an object of the present invention to provide a novel class of antibiotics which includes, inter alia, species having the basic nuclear structure of the penicillins but which are characterized by having a substituted methyl substituent at the 6-position of the .beta.-lactam ring. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as Staphylococcus aureus and Streptococcus pyogenes and gram negative bacteria such as E. coli and Klebsiella pneumoniae. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.